To be able to feed on blood, a mosquito vector modifies the response of the vertebrate host to injury, through a number of salivary factors that inhibit hemostasis and inflammation, and ultimately modify immune responses. These modifications are likely to enhance the ability of parasites and pathogens to invade the human host. The PI proposes four specific aims: (1) Characterize the molecules in Aedes aegypti and Anopheles stephensi saliva that modulate vertebrate immune responses (in a BALB/c mouse model). These molecules will be purified, cloned, sequenced and expressed as recombinant proteins. (2) Define the effects of mosquito saliva and salivary proteins on responses of B- and T- cells, macrophages, and Langerhans cells. The hypothesis that mosquito saliva creates a locally immunocompromized zone at the site of mosquito feeding will be tested. The influence of vector saliva on the development of Th1 (cytotoxic) Th2 (humoral) immune responses will be examined.. (3) Define the systemic or whole body immunomodulatory effects of mosquito saliva and individual salivary proteins. (4) Test the hypothesis that pathogens and parasites modify the saliva of vectors in a manner likely to enhance their vectorial efficacy. These studies are ultimately directed towards an understanding of the immunological consequences of vector feeding. An understanding of the immune environment into which vector-born pathogens and parasites are transmitted may lead to novel strategies for disrupting the transmission.